Lung cancer remains a major health problem for smokers who account for ~90% of the total cases. Despite the identification of several preventive agents and strategies, optimal prevention of lung cancer has not been achieved. More effective agents are therefore required that would safely achieve prevention without drastic side effects. Novel compounds which are rational modifications of natural products and follow a similar mechanism of action, but with enhanced potency, reduced toxicity, and lower dose requirement, may be clinically more relevant. Recently, our extensive structure-activity study involving naturally occurring and synthetic isothiocyanates and corresponding newly developed selenium analogs, the isoselenocyanates, have identified phenylbutyl isoselenocyanate (ISC-4;Ph-(CH2)4-N=C=Se) as the most efficacious anti-cancer agent. ISC-4 was found to be more effective than all other sulfur and selenium analogs studied, including corresponding phenylbutyl isothiocyanate (PBITC;[Ph-(CH2)4-N=C=S]), in inhibiting cell growth in various cancer cells, inducing apoptosis and cell cycle arrest, and inhibiting cell proliferation. It effectively inhibited PI3K/Akt signaling pathway and reduced melanoma tumor growth, by about 60%, without any systemic toxicity, at 0.76 5M dose at which PBITC did not show any reduction in tumor size. Our hypothesis is that ISC-4 retains mechanistic aspects of ITCs action (inhibit Phase I and induce Phase II enzymes;block cell-cycle progression and induce apoptosis) and include added chemopreventive effects of selenium, resulting in a potent yet safe drug for lung cancer prevention. Our preliminary studies supported our hypothesis and have shown ISC-4 to be a promising lung cancer chemopreventive agent. It significantly inhibited CYP450 enzyme activity, induced expression and activity of Phase II enzymes, and substantially reduced formation of pyridoxobutyl (pob)-DNA adducts in A/J mice. The goal of this study is to evaluate this rationally designed agent against NNK (a tobacco carcinogen) induced carcinogenesis and to understand if this activity is due to ISC-4 or one of its active metabolites. The objective of this proposal is to validate the efficacy of ISC-4 for inhibiting NNK induced lung cancer development. The specific aims to test our hypothesis and to accomplish the objectives of this application are (1) To determine the chemopreventive efficacy of ISC-4 in the A/J mouse lung cancer model, and (2) To determine the efficiency at which orally administered ISC-4 or its metabolites reach the target organ (lung) in A/J mice. We will use the experimental approach of evaluating effectiveness of dietary ISC-4 for inhibiting tumor development in A/J mice fed orally with NNK, and carry out the biodistribution study in A/J mice using [14C] ISC-4 to determine if ISC-4 or its metabolites reach the lung. These studies will begin establishing the potential of ISC-4 as lung cancer preventive agent. Long term, validation of ISC-4 as an effective and safe chemopreventive agent would reduce the chances of developing lung cancer in smokers/former smokers thereby directly decreasing the mortality incidence.